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CCN1 acutely increases nitric oxide production via integrin alpha(v)beta(3)-Akt-S6K-phosphorylation of endothelial nitric oxide synthase at the serine 1177 signaling axis

Title
CCN1 acutely increases nitric oxide production via integrin alpha(v)beta(3)-Akt-S6K-phosphorylation of endothelial nitric oxide synthase at the serine 1177 signaling axis
Authors
Hwang, SoojinLee, Hyeon-JuKim, GyungahWon, Kyung-JongPark, Yoon ShinJo, Inho
Ewha Authors
조인호이현주박윤신
SCOPUS Author ID
조인호scopus; 박윤신scopusscopus
Issue Date
2015
Journal Title
FREE RADICAL BIOLOGY AND MEDICINE
ISSN
0891-5849JCR Link1873-4596JCR Link
Citation
vol. 89, pp. 229 - 240
Keywords
Endothelial nitric oxide synthaseNitric oxidePhosphorylationCCN1IntegrinAktS6KVasodilationFree radicals
Publisher
ELSEVIER SCIENCE INC
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Although CCN1 (also known as cysteine-rich, angiogenic inducer 61, CYR61) has been reported to promote angiogenesis and neovascularization in endothelial cells (ECs), its effects on endothelial nitric oxide (NO) production have never been studied. Using human umbilical vein ECs, we investigated whether and how CCN1 regulates NO production. CCN1 acutely increased NO production in a time- and dose-dependent manner, which was accompanied by increased phosphorylation of endothelial NO synthase (eNOS) at serine 1177 (eNOS-Ser(1177)), but not that of eNOS-Thr(495) or eNOS-Ser(114). The level of total eNOS expression was unaltered. Treatment with either LY294002, a selective inhibitor of phosphoinositide 3-kinase known as an upstream kinase of Akt, or H-89, an inhibitor of protein kinase A, mitogen- and stress-activated protein kinase 1. Rho-associated protein kinase 2, and ribosomal protein S6 kinase (S6K), inhibited CCNI-stimulated eNOS-Ser(1177) phosphorylation and subsequent NO production. Ectopic expression of small interfering RNA against Akt and S6K significantly inhibited the effects of CCN1. Consistently, CCN1 increased the phosphorylation of Akt-Ser(473) and S6K-Thr(389). However, CCN1 did not alter the expression or secretion of VEGF, a known downstream factor of CCN1 and a potential upstream factor of Akt-mediated eNOS-Ser(1177) phosphorylation. Furthermore, neutralization of integrin alpha(v)beta(3) with corresponding antibody completely reversed all of the observed effects of CCN1. Moreover, CCN1 increased acetylcholine-induced relaxation in the rat aortas. Finally, we also found that CCN1-stimulated eNOS-Ser(1177) phosphorylation and NO production are true for other types of EC tested. In conclusion, CCN1 acutely increases NO production via activation of a signaling axis in integrin alpha(v)beta(3)-Akt-S6K-eNOS-Ser(1177) phosphorylation, suggesting an important role for CCN1 in vasodilation. (C) 2015 Elsevier Inc. All rights reserved.
DOI
10.1016/j.freeradbiomed.2015.08.005
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의학전문대학원 > 의학과 > Journal papers
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